Abstract This proposal investigates the role and impact of defective maintenance of protein homeostasis (proteostasis) of the aging brain, in the development and progression of Alzheimer?s disease. Disturbances in the systems that maintain neuronal proteostasis have been observed in Alzheimer?s disease, but the extent to which loss of proteostasis in the aging brain constitutes a risk factor for development of Alzheimer?s disease remains unknown. We will focus in chaperone-mediated autophagy (CMA), a protein quality control system that mediates selective degradation of cytosolic proteins in lysosomes. We have previously found that CMA activity decreases with age and that restoring CMA activity in old mice livers prevents their degeneration and preserves organ function. We propose that 1) the physiological decline of CMA with age increases the susceptibility of the aging brain to Alzheimer?s disease-related pathology and that 2) interventions to restore normal CMA activity in the aging brain will prevent or slow down progression of Alzheimer?s disease neurodegeneration. To test this hypothesis we intend to: 1) determine the spatiotemporal sequence of CMA changes in the aging brain to identify areas of higher susceptibility to proteotoxicity and points of ?no return? to proteostasis; 2) investigate if characteristics of the Alzheimer?s disease brain are phenocopied by neuronal CMA blockage; 3) test if genetic or chemical enhancement of CMA in the aging brain increases its resistance to AD-relevant proteotoxicity and improves neuronal homeostasis and function. Significance: This study will elucidate how functional decline of CMA contributes to brain aging and if it increases Alzheimer?s disease risk in the aging brain. Our findings could help in developing new approaches to preserve old brain homeostasis and function and reduce its risk to Alzheimer?s disease neuropathology.